Project Summary/Abstract Myalgic encephalomyelitis/chronic fatigue syndrome (referred to as CFS) is a debilitating disease characterized by unrelenting fatigue, post-exertional malaise, cognitive impairment, sleep problems, and pain. CFS disables 1-2.5 million Americans, and costs $17?24 billion annually. Clinical tests of CFS patients are typically normal. There are currently no molecular biomarkers or FDA-approved treatments. The cause of CFS is unknown. Recent data from ourselves and others show that CFS is a complex and misunderstood disease. This proposal is aimed at helping to understand the role of endogenous retrovirus (ERV) variations in the genetic predisposition for CFS. We propose a novel CFS model: polymorphic ERV insertions can be activated through demethylation, infectious agents, or both, and the resembled viral RNA triggers the inflammation pathway, ultimately leading to CFS. The co-contribution of genome-wide ERV variations and their activators is an unexplored research frontier and an important area for research in CFS. Here, we will focus on analyzing existing CFS genome, methylome, transcriptome, and microbiome data to identify ERV variations associated with CFS. Verifying ERV as a risk factor in CFS will aid in adoption of an antiviral or anti-inflammatory treatment or anti-inflammatory lifestyle. If ERV activators, such as demethylation or infectious agent triggers, are also found, research on this will eventually lead to new therapeutic intervention and prevention.